1,5-Diphenyl-4-methylpyrazole-3-carboxylic acid esters are described in particular in European Patent EP 576 357 and U.S. Pat. No. 5,624,941 to Barth et. al., both of which are hereby incorporated by reference. These esters are useful intermediates for preparing 1,5-diphenyl-4-methylpyrazole-3-carboxylic acid derivatives that are cannabinoid CB1 receptor antagonists.
It has now been found that the pyrazoles formed by the process of the present invention have an excellent affinity for the cannabinoid receptor and are therefore particularly valuable in the therapeutic areas for diseases and disorders in which cannabis is known to be involved.
The effects of cannabinoids are due to an interaction with specific high-affinity receptors present in the central nervous system (Devane et al., Molecular Pharmacology, 1988, 34, 605-613) and peripheral nervous system (Nye et al., The Journal of Pharmacology and Experimental Therapeutics, 1985, 234, 784-791; Kaminski et al., 1992, Molecular Pharmacology, 42, 736-742; Munro et al., Nature, 1993, 365, 61-65).
Characterization of this receptor has been made possible by the development of specific synthetic ligands such as the agonists WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or CP 55,940 (J. Pharmacol. Exp.
Ther., 1988, 247, 1046-1051).
The therapeutic indications of cannabinoids pertain to a variety of areas such as the immune system, the central nervous system and the cardiovascular or endocrine system (Hollister, Pharmacological Reviews, 1986, 38, 1-20, Renv and Sinha, Progress in Drug Research, 1991, 36, 71-114, Cannabinoid receptor expression in human leucocytes, European Journal of Biochemistry, 1993, 214, 173-180.
More particularly, compounds possessing an affinity for the cannabinoid receptor are useful as immunomodulators and psychotropic agents in treatment of thymic disorders, vomiting, myo-relaxation, various types of neuropathy, memory disorders, dyskinesia, migraine, asthma, epilepsy and glaucoma, in anticancer chemotherapy, in ischemia and angina, in orthostatic hypotension and in cardiac distress.
More particularly, ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyazol-3-carboxylate, described in European Patent EP 656 354, is a useful intermediate for preparing N-piperidino-5-4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, generically known as ribonabant.